Vincerx Pharma, Inc. announced promising clinical results from a Phase 1 NIH-sponsored study of enitociclib in combination with venetoclax and prednisone for the treatment of relapsed/refractory lymphoma. About Enitociclib: Enitociclib is a highly selective CDK9 inhibitor that prevents activation of RNA polymerase II, resulting in reduction of known oncogenes MYC and MCL1 (Frigault 2023). It is currently in a dose-escalation Phase 1 trial (NTC05371054), in collaboration with the National Institutes of Health, evaluating the combination of enitociclib, venetoclax, and prednisone in DLBCL and PTCL.

Two patients out of three (67%) with PTCL have had a best response of PR. A subject with angioimmunoblastic T-cell lymphoma treated in the first dose level of enitociclib had a PR with a 91% reduction in tumor burden and remains on study for follow-up. A second subject with PTCL who received the second dose level of enitociclib remains on study with a PR with an 86% reduction in pulmonary lesions and resolution of skin lesions.

In addition, on the second dose cohort of enitociclib, one patient with DH-DLBCL has achieved a PR after only one cycle of treatment?highlighting the faster response rate with the combination, compared with enitociclib monotherapy. Investigators are pleased with the safety profile of this novel combination (no DLTs have been observed so far) and continue with enrollment. Early-stage clinical studies (n=95) in patients with hematologic malignancies and solid tumors provided enitociclib monotherapy proof-of-concept.

Additional combination studies will be determined based on financing/partnering support. About VIP236: VIP236, the first-in-class small molecule drug conjugate (SMDC) from VersAptx Platform, consists of an avß3 integrin binder, a neutrophil elastase linker cleaved in the tumor microenvironment, and a camptothecin payload optimized for high permeability and low efflux. VIP236 was designed to deliver its payload to advanced/metastatic tumors that express avß3. Preclinical data show enhanced efficacy, independent of HER2 status, in patient-derived and cell line-derived gastric cancer models compared with ENHERTU®, an approved ADC.

VIP236 is being evaluated in a Phase 1 dose-escalation trial treating patients with advanced or metastatic solid tumors (NTC05371054). As VIP236 is a first-in-class drug, the Phase 1 trial is evaluating various dosing schedules. To date, 15 patients with advanced or metastatic disease that has relapsed or is refractory to standard of care have received VIP236; the early safety profile of once every three-week dosing is promising.

This schedule also shows early signs of clinical activity. The company expects to report preliminary clinical trial data in early 2024. About VIP943: VIP943, the first ADC from VersAptx platform, consists of an anti-CD123 antibody, a unique linker cleaved intracellularly by legumain, and a novel kinesin spindle protein inhibitor (KSPi) payload enhanced with CellTrapper® technology.

The increased therapeutic index has the potential to address challenges associated with many ADCs by improving efficacy and reducing severe toxicities. VIP943 is in a Phase 1 dose-escalation trial evaluating patients with relapsed/refractory acute myeloid leukemia, myelodysplastic syndrome, and B-cell acute lymphoblastic leukemia who have exhausted standard therapeutic options (NCT06034275). Preliminary pharmacokinetic data from the first cohort shows low levels of unconjugated payload (VIP716) in the circulation as predicted from preclinical experiments.

Reduced nonspecific release of payload is one of many features engineered into VIP943 to increase the therapeutic index compared with existing technologies. Company expects to expand into additional CD123-positive indications, including TP53 mutated AML, both as monotherapy and in combination, as safety and efficacy data are generated. Preliminary Phase 1 data are expected in mid-2024.

About VersAptx Platform: VersAptx is versatile and adaptable, next-generation bioconjugation platform. The modular nature of this innovative platform allows to combine different targeting, linker, and payload technologies to develop bespoke bioconjugates to address different cancer biologies. With this platform antibodies and small molecules can be used to target different tumor antigens, linkers can be designed to reduce non-specific release of the payload, cleave intracellularly or extracellularly, and conjugate to single or multiple payloads, and payloads can be designed with reduced permeability using CellTrapper® technology to ensure accumulation in cancer cells or to be permeable for release in the tumor microenvironment.

The VersAptx platform allows to optimize these technologies to a specific target and develop bioconjugates designed to address the safety and efficacy challenges of many ADCs and the needs of cancer patients.